Sandimmune

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Sandimmune

CLINICAL PHARMACOLOGY

Sandimmune® (cyclosporine)
is a potent immunosuppressive agent which in animals prolongs survival of
allogeneic transplants involving skin, heart, kidney, pancreas, bone marrow,
small intestine, and lung. Sandimmune® (cyclosporine) has been
demonstrated to suppress some humoral immunity and to a greater extent,
cell-mediated reactions such as allograft rejection, delayed hypersensitivity,
experimental allergic encephalomyelitis, Freund's adjuvant arthritis, and graft
vs. host disease in many animal species for a variety of organs.

Successful kidney, liver, and
heart allogeneic transplants have been performed in man using Sandimmune® (cyclosporine).

The exact mechanism of action
of Sandimmune® (cyclosporine) is not known. Experimental evidence
suggests that the effectiveness of cyclosporine is due to specific and
reversible inhibition of immunocompetent lymphocytes in the G0- or G1-phase of
the cell cycle. T-lymphocytes are preferentially inhibited. The T-helper cell
is the main target, although the T-suppressor cell may also be suppressed.
Sandimmune® (cyclosporine) also inhibits lymphokine production and
release including interleukin-2 or T-cell growth factor (TCGF).

No functional effects on
phagocytic (changes in enzyme secretions not altered, chemotactic migration of
granulocytes, macrophage migration, carbon clearance in vivo) or tumor cells
(growth rate, metastasis) can be detected in animals. Sandimmune® (cyclosporine)
does not cause bone marrow suppression in animal models or man.

The absorption of cyclosporine from
the gastrointestinal tract is incomplete and variable. Peak concentrations (Cmax)
in blood and plasma are achieved at about 3.5 hours. Cmax and area under the
plasma or blood concentration/time curve (AUC) increase with the administered
dose; for blood, the relationship is curvilinear (parabolic) between 0 and 1400
mg. As determined by a specific assay, Cmax is approximately 1.0 ng/mL/mg of
dose for plasma and 2.7-1.4 ng/mL/mg of dose for blood (for low to high doses).
Compared to an intravenous infusion, the absolute bioavailability of the oral
solution is approximately 30% based upon the results in 2 patients. The
bioavailability of Sandimmune® Soft Gelatin Capsules (cyclosporine
capsules, USP) is equivalent to Sandimmune® Oral Solution,
(cyclosporine oral solution, USP).

Cyclosporine is distributed
largely outside the blood volume. In blood, the distribution is concentration
dependent. Approximately 33%-47% is in plasma, 4%-9% in lymphocytes, 5%-12% in
granulocytes, and 41%-58% in erythrocytes. At high concentrations, the uptake
by leukocytes and erythrocytes becomes saturated. In plasma, approximately 90%
is bound to proteins, primarily lipoproteins.

The disposition of cyclosporine
from blood is biphasic with a terminal half-life of approximately 19 hours
(range: 10-27 hours). Elimination is primarily biliary with only 6% of the dose
excreted in the urine.

Cyclosporine is extensively metabolized but there is no
major metabolic pathway. Only 0.1% of the dose is excreted in the urine as
unchanged drug. Of 15 metabolites characterized in human urine, 9 have been
assigned structures. The major pathways consist of hydroxylation of the
Cγ-carbon of 2 of the leucine residues, Cη-carbon hydroxylation, and
cyclic ether formation (with oxidation of the double bond) in the side chain of
the amino acid 3-hydroxyl-N,4-dimethyl-L-2-amino-6-octenoic acid and Ndemethylation
of N-methyl leucine residues. Hydrolysis of the cyclic peptide chain or
conjugation of the aforementioned metabolites do not appear to be important
biotransformation pathways.

Specific Populations

Renal impairment

In a study performed in 4 subjects with end-stage renal
disease (creatinine clearance < 5 mL/min), an intravenous infusion of 3.5
mg/kg of cyclosporine over 4 hours administered at the end of a hemodialysis
session resulted in a mean volume of distribution (Vdss) of 3.49 L/kg and
systemic clearance (CL) of 0.369 L/hr/kg. This systemic CL (0.369 L/hr/kg) was
approximately two thirds of the mean systemic CL (0.56 L/hr/kg) of cyclosporine
in historical control subjects with normal renal function. In 5 liver
transplant patients, the mean clearance of cyclosporine on and off hemodialysis
was 463 mL/min and 398 mL/min, respectively. Less than 1% of the dose of
cyclosporine was recovered in the dialysate

Hepatic Impairment

Cyclosporine is extensively metabolized by the liver.
Since severe hepatic impairment may result in significantly increased
cyclosporine exposures, the dosage of cyclosporine may need to be reduced in
these patients.

Last reviewed on RxList: 5/17/2013
This monograph has been modified to include the generic and brand name in many instances.